Dr. Howland has financial interests with the following proprietary entity or entities producing health care goods or services as indicated below:

Grant/Research Support: Cyberonics; Medtronic; NeoSync

Accreditation Statement:

The University of Pittsburgh School of Medicine is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians.

The University of Pittsburgh School of Medicine designates this enduring material for a maximum of 1 AMA PRA Category 1 CreditsTM. Each physician should only claim credit commensurate with the extent of their participation in the activity. Other health care professionals are awarded (0.1) continuing education units (CEU) which are equivalent to 1 contact hours.

For your credit transcript, please access our website 4 weeks post-completion at http://ccehs.upmc.edu and follow the link to the Credit Transcript page. If you do not provide the last 5 digits of your SSN on the next page you will not be able to access a CME credit transcript. Providing your SSN is voluntary.

Transcripts

Good
morning, thank you very much. I’m happy
that everybody is here this morning, hope that you enjoy the program. I’m going
to start out this morning by focusing on devices, which is a very important
area in psychiatric research as well as in neurology and other branches of
medicine.

The
history of interventions based on surgical procedures in psychiatry is quite
checkered. In 1935 was one of the first
planned experiments, this was conducted in Europe. Egas Moniz, a European neurologist had
developed a notion about a way of treating psychiatric illness by selected cuts
and ablation procedures in the frontal lobes of the brain and he collaborated
with a neurosurgeon and they actually conducted a small study of 20 subjects.
And these subjects had depression, anxiety disorder, schizophrenia or bipolar
disorder, and actually published his experience with those 20 subjects in
1936.

In
the U.S. Walter Freeman brought the same procedure to the United States and
using much of the same surgical techniques worked with James Watts, a
neurosurgeon. But his interest was in
really developing something that could become office based. And that led to
sort of a deterioration in the quality of rendering the procedures and it’s often
referred to as his ice pick therapy because of the crudeness of the procedure
and really the deterioration of neurosurgical techniques. But his interest was in broadening it to a
wider scope of chronically ill patients with a variety of psychiatric illnesses.
And that led to really a burgeoning of these procedures up until the mid-1950s,
so about 20,000 individuals worldwide at some point had one of these procedures
for severe chronic intractable illnesses, and not necessarily related to
schizophrenia, it often involved individuals with mental retardation,
depressive illness and other ill defined groups of psychiatric patients.

In
1949 Moniz actually received the Nobel Prize for his earlier work. And the
procedures that he had done and his selection of patients in many ways was much
better than what Walter Freeman brought to the U.S. And unfortunately it was the work that Walter
Freeman did that was one of the downfalls of surgical procedures so that the
broad use of these interventions in any type of patient population, the type of
procedure that was done there was a lot of ill effects from it. So it really suffered from a reputation
standpoint in terms of how these patients were treated and what happened with
them. But obviously in the mid-1950s pharmacotherapy was introduced, Chlorpromazine,
Thorazine introduced in 1955 and then tricyclic antidepressants and
monoaminoxidase inhibitor antidepressants in the late 1950s and those drugs
ushered in really the era of modern psychopharmacology in the 1970s, 1980s and
even until today.

The
other problem with these types of procedures is it’s hard to do controlled
studies, and it’s hard to do modulations or changes with treatments to obtain
the best response. But these procedures
still exist, they can certainly be done and there are certain institutions,
Mass General and other places in this country and around the world that still
in selected, carefully selected patient populations with either treatment
resistant depression or treatment resistant obsessive compulsive disorder can
still do these types of procedures when all other fail – therapies have
failed. But really following on sort of
the history of psychosurgery is the notion that devices could be used as a
treatment for psychiatric illness. And for a lot of individuals devices to
treat a psychiatric or psychologic problem is kind of odd or foreign or
unusual, so I’m going to talk this morning about a variety of approaches using
different types of devices that are used to not create ablative lesions,
permanent lesions in the brain but do serve to modulate the function of
different brain regions in order to treat a variety of psychiatric illnesses.

So
I refer to this as therapeutic brain stimulation but it really should be
considered neuromodulation because with these types of stimulations you can
actually excite brain tissue or you can inhibit brain tissue but it’s entirely
intended to be reversible, potentially reversible and also modifiable. So that depending on what the device is and
the type of stimulation that you are using is you can actually adjust it much
like you would adjust the dose of a medication or change the focus of a
psychotherapy. And these have actually
been used in many respects to treat neurological disorders and in more recent
years to treat depression and also refractory OCD. But they also have some potential utility in
actually studying brain function because they don’t cause permanent lesions and
you can use different types of stimulation to assess what regions of the brain
have particular functions, either behavioral functions or motor functions.

Now
one of the most common types of therapeutic brain stimulations is ECT. This has been in use for many, many years, it
predated the era of modern psychopharmacology, it was actually developed during
the same year that psychosurgery was conducted in the 1930s and became of
greater use in the 1940s and since then. ECT is still considered the gold
standard treatment for treatment resistant depression so patients that have
failed any type of therapy, medication, psychotherapy, ECT is still sort of the
stand alone therapy in terms of what maybe potentially effective. It does suffer from its own bad reputation
although with qualified hands the administration of ECT really is considered very
safe and it can be very effective not only for treatment resistant depression
but psychotic depression and certain patient populations where you may have
particular concerns about the safety of medication. Women during pregnancy
suffering from severe psychiatric disorders and also geriatric patients may
greatly benefit from ECT and also have the benefit done safely. The most prominent adverse effect I think for
most people who are familiar with it are the cognitive effects. And part of – some of the studies it will
talk to today about using other devices are predicated based on using not
dissimilar principles to ECT but to try and minimize some of the adverse
effects of ECT.

Transcranial
Magnetic Stimulation, TMS, is another type of device based therapy. This
involves the use of a rapidly alternating magnetic current to induce a weak
electric current in underlying brain tissue. So this does not involve a brain
surgery but it does involve a stimulation by applying the TMS to different
brain regions. And this is one type of
device that has been used to study brain function but also have a lot of
therapeutic and potential therapeutic applications in neurology and psychiatry.
And psychiatry does have FDA approval of a particular device manufactured by
Neurostar. The labeling for the device are for individuals with depression that
have failed one antidepressant therapy, so the labeling is quite limited. But
the existing literature published studies looking at its utility in various
forms of depression suggest that there may be some benefit although not a very
strong benefit for patients with more extensive forms of treatment resistant
depression.

Surprisingly
the studies that have been done in anxiety disorders have not really shown a
significant benefit, but it has been applied also in other neurological
conditions and there are ongoing studies, for example auditory hallucinations
in patients suffering from schizophrenia, pain conditions, tinnitus and other disabling
neurological conditions.

Now
an offshoot of TMS is something referred to as Magnetic Seizure Therapy, this,
the intended purpose of Magnetic Seizure Therapy is to actually induce a
seizure. So with TMS the usual stimulation does not induce a seizure, but with
a high enough intensity the underlying brain tissue can be induced to propagate
a seizure. And the therapy behind MST is
to really limit the focal area of the seizure, at least the induction of the
seizure. And the idea is eventually to replace or to supplement the use of ECT
with a similar procedure with fewer adverse effects. There is very limited
human experimentation though with MST so it is investigational. But the principle is to use a type of TMS but
to induce a seizure, so it’s a mixture of TMS and what one intend to do with
the use of ECT. And again the patient population of interest would be patients
with refractory depression.

Another
type of therapy is called Cranial Electrotherapy Stimulation, and this actually
is an old treatment. The literature goes back many, many decades. The studies though are generally of poor
quality but this is a device that actually was approved by the FDA in 1979 for
anxiety, depression and insomnia. But
the approval of this device is based on old regulatory guidelines that were in
place in the 1970s and it’s not clear to me today whether this type of a device
based on the available studies would necessarily receive FDA approval. It is a
low risk device and the administration of CES is quite safe, there are few if
any side effects. And this involves the
use of very low pulsed micro currents and typically the treatment would be
administered by ear clips and the device would pass a very low essentially
undetectable current through the brain, and probably the only thing that a
patient might experience is a tingling where the point contact is with the
electrodes. So this is a device that
actually one could use, you could certainly find a practitioner or a
manufacturer of the device, but my reading of the literature would suggest is
that the studies that you know are suggesting some benefit for depressive
disorders, anxiety disorders, etc really are not high quality studies. So you have a device that’s approved, a low
risk but not necessarily effective for patients with more severe types of
depression or anxiety disorders or patients with treatment resistant
conditions.

Another
type of stimulation is Transcranial Direct Current Stimulation and this is
somewhat different than CES, this is also investigational. There is one pilot
study that demonstrated some benefit in patients with treatment resistant
depression, there was also more recently an unpublished clinical trial, a
randomized sham controlled trial in 64 patients with treatment resistant
depression suggesting benefit to this type of intervention. That study is
recent and I’m not sure that it’s yet been published but it is in Prowse. And this is predicated based again on notions
of inducing electric currents, the intent is not to cause a seizure as a part
of its therapeutic benefit and the types of side effects that one would experience
with that qualitatively and quantitatively are different than what are
experienced with ECT, in particular adverse cognitive effects.

And
with this type of procedure it’s applied externally and you need two electrodes
and typically one would be placed on the motor cortex near the crown and then a
second electrode would be placed above the eye so the contralateral orbit, and
this low level direct constant current is then passed from one electrode to the
other and the therapeutic benefit in some ways based on the administration of
that low level current. Some muscle
contractions and perhaps some muscle pain are a potential side effect. It is
possible that you could induce a seizure although with the currents that are
used that would be considered unlikely.

Another
type of procedure, this is actually related to ECT because the machine that’s
used to induce the electric current is the same type of machine that’s used to
administer electroconvulsive therapy.
And the principle of it though is to focal, focalize the current to a
particular brain region. And it does so
by altering the current so that it goes in one direction and also the theory is
that if you use a larger electrode and then a smaller electrode like a funnel
the current will be funneled to a particular area of the brain. So this is an
experimental procedure investigational, most of the work and there is some
human experiments you know looking at how the electrodes are placed but no
clinical studies. But the intent of this
would be to use it as sort of a modified or alternative type of ECT, because
with a high enough administered current and voltage you can actually induce a
seizure so that there are two alternative forms, one that does not cause a
seizure and the other than would be intended to cause a seizure. But the point of this procedure is really to
limit the current to a particular brain region and to avoid sort of the broad
spread of the current that might be associated with adverse effects, especially
the cognitive effects that you see with ECT.
The work that’s been done with FEAST inducing seizures has actually only
been done in animals studying this type of an effect, but the principle again
is the same.

Now
the frontal lobe of the brain is quite important and some of the procedures,
TMS for example, are predicated based on understanding what happens in the
frontal lobes in individuals with depression.
The types of psychosurgical procedures that were developed in the 1930s
were based on the notion that the fibers connecting the frontal lobes to the
deeper structure of the brain in some way were functioning abnormally and by
severing or cutting those fibers that you may induce an improvement in the
underlying psychiatric symptoms, depression, anxiety. So there is some relationship between the
older procedures and some of the newer surgical based procedures in what are
done with things like TMS. Now TMS is
focused on an area of the brain in the dorsolateral prefrontal cortex, and this
area especially on the left side of the brain is relatively underactive and
that part of the brain may be relevant for understanding mood symptoms as well
as cognitive symptoms. So TMS is based on the notion that stimulating that
particular region of the brain may lead to a clinical improvement. And so as I mentioned a device manufactured
by Neurostar currently had FDA approval and is currently labeled to be
available for patients with depression that have failed a single antidepressant
therapy.

Curiously
there are differences between the right and left dorsolateral prefrontal
cortex. So the usual high intensity TMS stimulation is directed at the left
region, a lower intensity stimulation of the right dorsolateral prefrontal
cortex also has antidepressant effects as well, so there does seem to be a
bilateral difference in that type of stimulation. So high frequency is
effective on the left side, low frequency is effective on the right side
although the device that’s approved in the labeling is indicated for
application to the left DL PFC.

Now
a modified type of TMS is investigational. This uses the same type of
stimulation, rotating magnets, but the intensity of the magnetic stimulation is
less than what is intended with TMS. It
also is applied to both sides of the brain, so the brain region is different
than TMS, standard TMS and also the intensity of the stimulation. And this is intended to change cortical
frequencies and oscillatory frequencies and in particular the alpha band waves. So the type of treatment, and this is a
schematic of how this type of TMS is administered, involves 3 magnets. One is placed on the crown of the skull, the
other the middle of the forehead just above the eye and then the third one in
between so it’s a midline application, so it causes TMS stimulation to both hemispheres,
so it’s not directed at the left dorsolateral prefrontal cortex. And the intent
of this lower level stimulation because it’s tied to the alpha frequency that’s
measured for each individual patient is to try and tune those frequencies and
to try and reset oscillatory frequencies throughout the brain through this type
of stimulation.

So
this is what the device actually looks like.
A patient would lie on the table and their head fits neatly, so this is
above the forehead and the other magnet is at the crown and then the middle
one, so it covers it neatly. And patients would lie there and have this
treatment administered. At the beginning
the device will actually measure a patient’s alpha wave, and then the TMS is
programmed to the same frequency of that individual patient’s alpha frequency.
And then they would sit in the device for 30 minutes and they have to be awake
to maintain the alpha frequency but they have the stimulation. And the belief
is that that type of stimulation over time has some type of an effect on
oscillating frequencies throughout the brain that may be important for
regulating or connecting disparate brain regions. And some of the work hasn’t been publicized
or published, but it is based on notions about disconnected brain regions and
the importance of different EEG wave forms in terms of how different regions
are connected and making changes in terms of being on or being off. So the
intent of synchronized TMS is very different than standard repetitive TMS in
terms of its application and the intensity.

Now
there is a published study, this was actually presented at a meeting as an
abstract, a pilot study, it was sham controlled using STMS and subjects with
major depression for 4 weeks. So half the subjects had the device activated,
the other half the device was not activated. And it was conducted in a double
blind and what the pilot study showed is that the act of treatment had an
antidepressant effect in terms of response rates and remission rates compared
to the sham treatment. So this took it
from principle to an actual clinical population. And this has led to a larger collaborative
study and we are participating in it in Pittsburgh. This is focusing on the use
of STMS in patients with major depression, it’s a double blind placebo, or sham
controlled study. And this is focused on patients with a limited form of
treatment resistant depression. So it’s
using the same type of device with the same application but in a little bit
different patient population.

So
we’ve already enrolled one subject in Pittsburgh and the inclusion criteria for
this study are adults suffering from major depression, no history of bipolar
disorder, no history of psychosis. And patients cannot be considered
chronically depressed, so their current episode duration has to be less than 2
years. And the population for this
particular study was based on the current labeled population from the FDA
approved TMS device, so patients that had failed one antidepressant therapy who
were suffering from major depression are eligible for this particular project.
So it’s a very narrow patient population, they are not treatment naïve and they
also do not have extensive histories of having failed a variety of
antidepressant therapies. But it’s
similar to what is currently approved in the labeling for the TMS device on the
market.

And
patients that are eligible would discontinue their current antidepressant
medication. At the beginning visit they
would sit in the device and have their individual alpha frequency analyzed and
then the device is programmed to match that. And because it’s a sham control
one of the devices is active, the other device is not active and there is no
way of distinguishing the two. When STMS is administered you don’t feel
anything. In theory you can have
headache, muscle contraction, but the intensity of the TMS stimulus is so low
that you would rarely expect those types of effects. So the blinding for this
is somewhat easier compared to other types of device interventions.

One
of the other difficulties in doing this is TMS typically is administered 5 days
a week over a period of weeks. So the
current approved TMS device was based on studies where patients received the
treatments 5 days a week for up to 6 weeks.
Then they actually have to come to the clinic, so it’s very different
than doing a drug study where somebody takes a medication at home or even very
different than psychotherapy study where a patient might come in twice a week
for a period of weeks. So this is sort of a labor intensive intervention for
the approved treatment, but also for the study from the patient’s
perspective. And then in this particular
study patients who receive the active treatment and there is an optional open
label phase where again the blind is not broken so we don’t know whether the
subjects have had active STMS or not, but will receive active treatment over a
period of time. And this is randomized, double blind placebo controlled.

Now
I’m going to focus a little bit about devices that do involve neurosurgical
procedures, but again these types of procedures are not intended to cause
lesions or ablations in brain regions, so they do involve surgery often to
implant electrodes or the pulse generators, the pacemakers to generate the type
of stimulus that’s used. And the ones that we are familiar with are Vagus Nerve
Stimulation, Cortical Brain Stimulation and Deep Brain Stimulation. VNS and DBS have certain FDA labeled
indications, each of them has also been studied in depression. Cortical Brain Stimulation is considered
investigational, it’s been studied in depression, I’ll present some of the
results of the study that we participated in.

Vagus
Nerve Stimulation may be something that you are all familiar with to some
degree or another. This is FDA approved for
treating refractory epilepsy, certain subtypes of epilepsy as well as treatment
resistant depression. And this involves
a procedure where the electrode is placed in the vagus nerve and the vagus
nerve runs up through the neck, so it doesn’t involve a procedure to the brain
itself. And the device, the pulse generator is connected to the vagus
nerve. And the principle is that the
propagation of the current causes a direct and indirect stimulation of various
brain regions, so this is an antiseizure therapy, it doesn’t induce
seizures. But the changes that often
occur, chemical changes and probably regional changes in different parts of the
brain that are relevant to mood regulation are altered, and so based on this
chronic intermittent stimulation of the vagus nerve is that there are
antidepressant benefits. So the device
is FDA approved for treatment resistant depression.

There
are a number of pilot studies that have been conducted and most of these have
been published in a variety of conditions ranging from treatment resistant
anxiety disorders to Alzheimer’s disease, a study done in Sweden because of the
potential positive cognitive effects of stimulation of the vagus nerve. The most recent study though in depression is
referred to as D21 and we participated in that in Pittsburgh.

This
is a study looking at 3 different dose levels of vagus nerve stimulation in
patients with treatment resistant depression.
So this study was randomized and double blind and patients were
randomized to 3 different stimulations, low, high and intermediate stimulation
and these are the baseline characteristics, which is really to illustrate how
sick this patient population is. When
you look at the percentage of patients that have received ECT in the past or in
their current episode is very high, 50%, without an adequate response. In the past more than 90% of the patients had
failed more than 6 different types of antidepressant therapies, and in the
current episode down here about 80% of the patients had failed 6 or more
antidepressant treatments in their current episode. And these patients in their current episode
were depressed for an average of 9 years.
So they were very chronically ill, severely ill and also very refractory
to treatment. And so these were patients randomized to 3 different dose levels
of VNS.

So
the acute phase was through 22 weeks and there were different assessments that
were done measuring improvement in depression symptoms. And what you see is that there is a numerical
difference between high, middle and low doses but it wasn’t statistically
significant. And the study enrolled more
than 200 subjects, so there was a hint that higher stimulation doses were more
effective but it really didn’t achieve statistical significance. And this was after 22 weeks. And these are the remission rates, again
showing numerical differences favoring the higher stimulation but no
statistically significant difference among the three different dose levels.

And
this is then tracking patients over time using one of the depression measures.
So after the acute phase patients continued for up to nearly a year’s time, and
what this study also demonstrated is over time there really wasn’t very much of
a difference in the three different dose levels. But what is known from prior
VNS studies and what this study confirmed is that there seemed to be an
accumulating benefit over time. So that
over time patients with chronic treatment resistant depression tended to get
better.

And
one of the things about treating treatment resistant depression with
pharmacotherapy is that there is a high risk of relapsing. It’s not uncommon
for patients with TRD to show some initial benefit to a new treatment but then
that benefit peters out or dissipates over time. So the persistence of a
benefit over time is really one of the difficulties in managing this type of
patient population. So this was the
analysis looking at the persistence, comparing what happened at 22 weeks versus
50 weeks. And what the analysis showed is that a significant proportion, the
majority of the patients were able to maintain their 22 week benefit for up to
a year’s time. and again this is I think very important in terms of thinking
about what happens with these types of patients over time when they are treated
with non-device based therapies. You might find something that works for a
period of time but then lose the benefit and you have to go through these
iterative cycles of trying different treatments or different treatment
combinations. And there really again
wasn’t much of a hint that there were different dose effects over time although
there was a suggestion that the patients in the lowest stimulation dose were
less likely to maintain their initial benefit from week 22 to week 50. So in the clinical use of VNS one might
adjust the stimulation to higher and higher levels over time to try and either
enhance the benefit or to maintain the benefit.

Now
like all treatments there are adverse effects with VNS, but VNS has actually
been used in many thousands of patients around the world for epilepsy and now
depression, so there really is a lot of human experience with VNS. And really for the most part it’s a very well
tolerated treatment. There aren’t any measurably severe significant side
effects, and over time even the side effects that do occur, the voice
alteration, etc. tolerance can develop to that.
So over time one can adjust the stimulation to higher and higher levels
to try and gain a better response, but over time side effects typically do not
multiply or increase in either their severity or their persistence.

Now
Cortical Brain Stimulation is another type of stimulation. This involves a
surgery and it involves placing electrodes on the surface of the brain, so
there is one surgical incision to place the pulse generator in the chest and
then a second one where the electrode array is placed on the surface of the
brain. It’s investigational and it’s
been looked at in stroke, tinnitus and also depression so the location of the
electrode array will depend on the indication.
And this is how it’s setup, the pulse generator and the electrode
array. For depression where the
electrodes are placed on the surface of the brain is the left dorsolateral
prefrontal cortex, so the same region of the brain that is the target of
interest with TMS. And the theory behind
using a surgical intervention is to bring the stimulation in more direct
contact with the brain because the administration of TMS has to go through the
scalp and the skull and that’s resistance.
And so by the time TMS reaches the brain the intensity may be either
dissipated and weakened at that area or it may be spread through different
areas of the brain. So the principle is
really to apply the same stimulation but more directly to that brain region.

And
the other problem with TMS is that it requires a constant application 5 days a
week for 6 weeks during acute treatment, it’s hard to do maintenance treatment
with something like that. So in theory
using a surgical intervention providing a similar type of stimulation to the
brain can be done automatically through this battery generated pulse
generator. So it was really designed to
sort of replicate what TMS does but to make it more of a long term therapy but
also for more, for a more varied treatment resistant patient population.

So
this study was actually just published this month in the Journal
Neurosurgery. This was a pilot
feasibility study of 12 subjects and the patient population in terms of
severity is similar to what we saw with VNS, so they are chronically depressed,
an average of about 7 years, they’d failed a large number of antidepressant and
psychotherapies all targeted at depression. So this population is a lot messier
than the typical patient population that would be used for TMS.

And
so in the first phase of the study patients were treated for 8 weeks and this
was a sham controlled, so some of the patients had the device activated, the
other half the device was not activated.
After 8 weeks it was activated for all subjects and they went through
another 8 weeks and then long term treatment.
So these are percentage changes in depression. During the acute sham
controlled phase there was no statistically significant difference between
active treatment and sham treatment although there was a small numerical
difference. But you have to keep in mind
that this was a pilot study, it was not intended to show efficacy it was
primarily focused on safety features. But also the sample size of 12 subjects
would make it very, very difficult unless there was a very large magnitude
difference in benefits. What we also
found over time was that there were small persistent changes over time,
suggesting that this therapy could be beneficial for patients suffering from
chronic treatment resistant depression.

And
like Vagus Nerve Stimulation, Deep Brain Stimulation there is certain side
effects, but the targeted area the risk of seizures is very unlikely because
the stimulus that’s actually applied to the surface of the brain is fairly
weak. You could turn up the juice enough and eventually you could induce a
seizure but how the device is programed is really limited to stimulating that
cortical surface of the brain. Adverse
effects in terms of changes in mood were not observed in the pilot study and
also no adverse cognitive effects.

And
then finally Deep Brain Stimulation, this one also involves implanted
electrodes but rather than being placed on the surface of the brain are
directed at various targets in deeper regions of the brain. But like VNS and
Cortical Stimulation are driven by pulse generators, so an external stimulation
to the brain. But this is focusing on brain regions. And this has actually been
studied quite extensively. So again the
pulse generator is because the stimulation is in both hemispheres of the brain
rather than a particular single region, involves two electrodes.

And
in order to direct the electrode to a particular target deep inside the brain
one has to direct the electrode in 3-dimensions. So a stereotactic device is placed on the
skull and a computer guided needle is inserted, so a burr hole is drilled in
the skull creating a space and then based on the particular location that’s
determined in 3-dimensions the electrode is then placed into the target of
interest. So for different indications
it may be the motor nuclei of the brain for treating Parkinson’s disease or
tremors, for depression there are several areas of interest.

And
then for the procedure once the electrodes are in place but before the pulse
generator is planted the patient wakes up and clinical assessments are done. So
if one is treating somebody for Parkinson’s disease one would do clinical
assessments for tremors and other aspects to determine whether the stimulation
seems to have any type of acute affect.
For depression we look for acute mood changes. And the reason is really
to make sure that an area that would be considered hot or potentially
beneficial has been identified but also to identify any particular acute
adverse effects. So if you turn the
stimulation on and a person has a very unusual or noxious effect is that you
learn that based on doing a systematic assessment. So this is all done within
the operating room. And once that’s been determined then the pulse generators
are implanted in the chest and they are connected to the electrodes.

And
this is showing what happens after the electrodes are implanted, so you can see
the insertion, the leads are tunneled under on top of the – under the scalp and
on top of the skull and through the neck and are connected to the pulse
generators in the chest. And then the
pulse generators can be programmed and they can be adjusted over time. So again the intent of Deep Brain Stimulation
is not to cause a lesion but to cause some type of disruption in the
functioning of a circuit or a brain region.
And because you can adjust the stimulation you can change the type of
stimulation, so the intent is not to be destructive but to cause some of a
modulation, whether you are modulating the tremors and other symptoms of
Parkinson’s disease or to change the mood effects of a patient with depression
or obsessive compulsive disorder.

And
it is FDA approved for certain neurological conditions, it also has a
humanitarian device exemption approval for clinical use in refractory obsessive
compulsive disorder. It’s currently being studied or has been studied for
treatment resistant depression. It also
has potential applications and there are small studies in different types of
conditions, Turret’s syndrome, tardive dyskinesia, other types of neurological
conditions. And the reason the DBS can
be used in such a wide variety of neurological and psychiatric conditions is
based on the fact that you can target the electrodes to different underlying
brain regions. So in contrast with TMS it’s based on the notion that the
dorsolateral prefrontal cortex is under-functioning in some way, the same thing
with Cortical Stimulation. In Vagus
Nerve Stimulation a single procedure involving stimulation of a single nerve,
but with DBS depending on what the clinical indication is the brain region if
it’s been identified can be targeted. And as I mentioned at the beginning one
can do controlled studies where the device is active or not active to determine
whether it’s efficacious.

With
lesion studies you create the lesion and that’s that, you really can’t do a
control and it’s very difficult to make modulations or adjustments. So doing
studies to identify the therapeutic benefits of lesion studies is very, very
difficult and it’s difficult to interpret the outcome.

So
two areas of interest in depression in particular, an area 25, CG25 and also
the nucleus accumbens is in the region of the ventral capsule, ventral
striatum. And these are two areas that there have been a number of studies
conducted. The first was publicized in
2005, the group by Helen Mayberg and her colleagues initially in Canada and
then in Atlanta was focusing on a very chronically and severely ill patient
population with treatment resistant depression.
Their initial publication in 2005 and then a follow-up 6 months in 2008,
this involved 20 subjects that were implanted. And you can see the response
rates and the remission rates after 6 months and after 12 months.

And
then earlier this year a longer term follow-up 3 to 6 years was published in
the American Journal of Psychiatry again showed a fairly significant persistent
benefit in terms of response and remission rates, again keeping in mind that
these are very ill patients in terms of their treatment history and
nonresponse, chronicity and disability, so these types of response and
remission rates are quite healthy for this patient population. For a non-chronic, non-treatment resistant
depressed population a drug study showing these benefits you know would probably
be not very remarkable, but for this type of patient population this is quite
good.

The
other area of interest is the nucleus accumbens, last year a study published,
this was a European group, an open study in a similar patient population
suggested benefits for patients with TRD.
Similar response and remission rates after 12 months.

And
then another pilot study was conducted by another group, a group that we’ve
collaborated with, again similar brain region.
This involved 15 subjects and over time there was a significant response
and remission rate to the use of DBS targeted the nucleus accumbens. And that led to a larger study that we
participated in Pittsburgh, it was designed as a feasibility study involving 30
subjects, double blind and sham controlled involving the same group at
Cleveland but also some other centers.
And these patients were very ill based on their treatment history, the
severity of their depression and also the chronicity of their depression. So this study has been completed but I’m not
able to report on the results yet because they haven’t been released. I was
hoping that it would be available by the time of the conference. So this is the most recent DBS study for
treatment resistant depression that’s been completed but the results are not
yet publicly available.

And
DBS also has potential side effects in terms of surgical risk, it does have
more of a risk of internal bleeding in the deeper ranges of the brain is also
seizures, but again like VNS there is a lot of human experience with DBS
because it’s been used for a variety of neurological conditions and also some
limited use in patients with refractory OCD.
Because it does involve the implantation of these electrodes using an
MRI scanner would be contraindicated, using therapeutic ultrasound is
contraindicated as well. So you have to be careful about the use of certain
diagnostic procedures with patients that have DBS implanted.

Then
I’m going to finish by kind of putting these devices in perspective. One of the largest clinical studies in
depression was STAR*D, and STAR*D involved patients with major depression that
were treated initially with a single medication and treatment failures then
went through different levels of treatment.
So to think about what happened in STAR*D these are the percentage of
patients that showed a remission after their first treatment, and
non-responders went to Level 2, these are their remission rates and then after
Level 3 and after Level 4. According to
current labeling patients that have failed Level 1 treatment would be eligible
to receive TMS treatment, although clinically based on literature there is some
suggestion that patients that had failed 2 or 3 treatments might benefit from
TMS. But for this type of device it
would be targeted for this range of the pharmacologic treatment resistant
patient population.

Now
Vagus Nerve Stimulation, according to the current labeling are patients that
failed at least 4 different antidepressant therapies, and that might include
ECT. So according to that labeling
patients that would be eligible for VNS would be down here, having gone through
a range of at least 4 therapies.

Now
DBS is not approved for treatment resistant depression but if any of the
studies are successful would be likely to be indicated for patients at that end
of the spectrum as well, patients that have had extensive treatment failures
and possibly including patients that have been treated with and have failed
electroconvulsive therapy. Now DBS is
indicated, has an indication for treatment resistant obsessive compulsive
disorder, and that label mentions having failed at least 3 different SSRI
antidepressant medications. So that would be patients treated 1, 2 and then 3
might be potentially eligible to receive DBS for OCD.

So
this really I think puts it in perspective in terms of where a device might fit
in based on the labeling, or the types of studies that are conducted. But for
the more invasive procedures you are really dealing with patients that have
failed a variety of medication therapies and combination therapies as well as
psychotherapies. And then if you add ECT to the mix some patients may not like
ECT, so for ECT intolerant patients there is also I think a potential role for
some of these devices.

So
just wanting to acknowledge the people that I work with, we’ve done device
studies for about 10 years now and we’ve actually done 5 different device
studies. Doing device studies is very, very difficult from a clinical
standpoint and a regulatory standpoint, so it does involve a lot of man hours
of work to be able to do the studies, to do the double blinding and the
assessments and also all of the regulatory paperwork and also ethical reviews.
So I want to acknowledge and thank all of the people that I work with who have
been involved in different aspects of these studies. Thank you very much.

Presenter

Robert H. Howland, MD

Dr. Howland is an Associate Professor of Psychiatry with clinical and research experience in psychopharmacology, psychotherapy, and novel and alternative therapies for mood and anxiety disorders.Specialty: PsychiatrySub Specialty: Geriatric PsychiatryBoard Certifications: Geriatric ...View Full Profile

In addition, you will need an internet connection with sufficient bandwidth. Our videos stream at 250Kbps or 650Kbps,and will adjust on your bandwidth, but we recommend bandwidth of 1000Kbps or higher the best playback.